Oxazolidine dione derivatives

ABSTRACT

Compounds of the formula: ##STR1## or tautomeric forms and a pharmaceutically acceptable salt, and pharmaceutically acceptable solvates thereof, wherein: 
     A 1  is a substituted or unsubstituted oxazole substituted by up to 4 substituents selected from the group consisting of C 1-6  -alkyl, C 1-6  -alkoxy, phenyl, and halogen or any two substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a benzene ring, and wherein the carbon atoms of the benzene ring represented by the said two substituents are unsubstituted or substituted with up to three groups selected from halogen, C 1-6  -alkyl, phenyl, C 1-6  -alkoxy, halo-C 1-6  -alkyl, hydroxy, amino, nitro, carboxy, C 1-6  -alkoxycarbonyl, C 1-6  -alkoxycarbonyl-C 1-6  -alkyl, C 1-6  -alkylcarbonyloxy, and C 1-5  -alkylcarbonyl; 
     R l  is a hydrogen atom, a C 1-6  -alkyl group, a C 1-6  -alkylcarbonyloxy group, a phenyl-C 1-6  -alkyl group, wherein the phenyl moiety may be substituted or unsubstituted, or a substituted or unsubstituted phenyl group, wherein the said phenyl groups may be substituted with up to three groups selected from halogen, C 1-6  -alkyl, phenyl, C 1-6  -alkoxy, halo-C 1-6  -alkyl, hydroxy, amino, nitro, carboxy, C 1-6  -alkoxycarbonyl, C 1-6  -alkoxycarbonyl-C 1-6  -alkyl, C 1-6  -alkylcarbonyloxy, and C 1-6  -alkylcarbonyl; 
     A 2  is a benzene ring having in total up to five substituents wherein three optional substituents are selected from halogen, C 1-6  -alkyl, phenyl, C 1-6  -alkoxy, halo-C 1-6  -alkyl, hydroxy, amino, nitro, carboxy, C 1-6  -alkoxycarbonyl. C 1-6  -alkoxycarbonyl-C 1-6  -alkyl, C 1-6  -alkylcarbonyloxy, and C 1-6  -alkylcarbonyl; and n is an integer from 2 to 6, are disclosed as hypoglycemics, hypolipidemics and antihypertensives.

OXAZOLIDINE DIONE DERIVATIVES

This invention relates to certain substituted oxazolidinedionederivatives, to a process for preparing such compounds, topharmaceutical compositions containing such compounds and to the use ofsuch compounds and compositions in medicine.

European Patent Applications, Publication Numbers 0008203, 0139421,0155845, 0177353, 0193256, 0207581, 0208420 and 0306228 relate tothiazolidinedione derivatives which are disclosed as havinghypoglycaemic and hypolipidaemic activity. Chem. Pharm. Bull 30 (10)3580-3600 also relates to certain thiazolidinedione derivatives havinghypoglycaemic and hypolipidaemic activities.

It has now surprisingly been discovered that certain novelsubstituted-oxazolidinedione derivatives show improved blood-glucoselowering activity and they are therefore of potential use in thetreatment and/or prophylaxis of hyperglycaemia and are of particular usein the treatment of Type II diabetes.

These compounds are also indicated to be of potential use for thetreatment and/or prophylaxis of other diseases includinghyperlipidaemia, hypertension, cardiovascular disease and certain eatingdisorders.

Accordingly, the present invention provides a compound of formula (I):##STR2## or a tautomeric form thereof and/or a pharmaceuticallyacceptable salt thereof, and/or a pharmaceutically acceptable solvatethereof, wherein:

A¹ represents a substituted or unsubstituted aromatic heterocyclylgroup;

R¹ represents a hydrogen atom, an alkyl group, an acyl group, an aralkylgroup, wherein the aryl moiety may be substituted or unsubstituted, or asubstituted or unsubstituted aryl group;

A² represents a benzene ring having in total up to five substituents;and

n represents an integer in the range of from 2 to 6.

Suitable aromatic heterocyclyl groups include substituted orunsubstituted, single or fused ring aromatic heterocyclyl groupscomprising up to 4 hetero atoms in each ring selected from oxygen,sulphur or nitrogen.

Favoured aromatic heterocyclyl groups include substituted orunsubstituted single ring aromatic heterocyclyl groups having 4 to 7ring atoms, preferably 5 or 6 ring atoms.

In particular, the aromatic heterocyclyl group comprises 1, 2 or 3heteroatoms, especially 1 or 2, selected from oxygen, sulphur ornitrogen.

Suitable values for A¹ when it represents a 5- membered aromaticheterocyclyl group include thiazolyl and oxazolyl, especially oxazolyl.

Suitable values for A¹ when it represents a 6- membered aromaticheterocyclyl group include pyridyl or pyrimidinyl.

Preferably, A¹ represents a moiety of formula (a), (b) or (c): ##STR3##wherein: R⁴ and R⁵ each independently represents a hydrogen atom, analkyl group or a substituted or unsubstituted aryl group or when R⁴ andR⁵ are each attached to adjacent carbon atoms, then R⁴ and R⁵ togetherwith the carbon atoms to which they are attached form a benzene ringwherein each carbon atom represented by R⁴ and R⁵ together may besubstituted or unsubstituted; and in the moiety of formula (a) Xrepresents oxygen or sulphur.

Aptly, A¹ represents a moiety of the abovedefined formula (a).

Aptly, A¹ represents a moiety of the abovedefined formula (b).

Aptly, A¹ represents a moiety of the abovedefined formula (c).

In one favoured aspect R⁴ and R⁵ together represent a moiety of formula(d): ##STR4## wherein R⁶ and R⁷ each independently represent hydrogen,halogen, substituted or unsubstituted alkyl or alkoxy.

Suitably, R⁶ and R⁷ each independently represent hydrogen, halogen,alkyl or alkoxy.

Favourably, R⁶ represents hydrogen. Favourably, R⁷ represents hydrogen.

Preferably, R⁶ and R⁷ both represent hydrogen.

In a further favoured aspect R⁴ and R⁵ each independently representhydrogen, alkyl or a substituted or unsubstituted phenyl group and morefavourably, R⁴ and R⁵ each independently represent hydrogen, alkyl orphenyl.

Preferably, for the moiety of formula (a), R⁴ and R⁵ together representthe moiety of formula (d).

Preferably, for the moieties of formula (b) or (c), R⁴ and R⁵ bothrepresent hydrogen.

Suitable substituents for the moiety A² include halogen, substituted orunsubstituted alkyl or alkoxy.

Favourably, A² represents a moiety of formula (e): ##STR5## wherein R⁸and R⁹ each independently represent hydrogen, halogen, substituted orunsubstituted alkyl or alkoxy.

Suitably, R⁸ and R⁹ each independently represent hydrogen, halogen,alkyl or alkoxy.

Preferably, R⁸ and R⁹ each represent hydrogen.

Favourably, X represents oxygen. Favourably, X represents sulphur.

In one preferred aspect the present invention provides a class ofcompounds, which fall wholly within the scope of formula (I), of formula(II): ##STR6## or a tautomeric form thereof, and/or a pharmaceuticallyacceptable salt thereof and/or a pharmaceutically acceptable solvatethereof, wherein A¹, R¹ and n are as defined in relation to formula (I)and R⁸ and R⁹ are as defined in relation to formula (e).

Suitably, n represents an integer 2, 3 or 4, notably 2 or 3 andespecially 2.

Suitably, R¹ represents hydrogen alkyl, acyl, especially acetyl, orbenzyl.

Preferably, R¹ represents a methyl group.

As indicated above a compound of formula (I) may exist in one of severaltautomeric forms, all of which are encompassed by the present invention.It will be appreciated that the present invention encompasses all of theisomeric forms of the compounds of formula (I) and the pharmaceuticallyacceptable salts thereof, including any stereoisomeric forms thereof,whether as individual isomers or as mixtures of isomers.

Suitable substituents for any heterocyclyl group include up to 4substituents selected from the group consisting of: alkyl, alkoxy, aryland halogen or any two substituents on adjacent carbon atoms, togetherwith the carbon atoms to which they are attached, may form an arylgroup, preferably a benzene ring, and wherein the carbon atoms of thearyl group represented by the said two substituents may themselves besubstituted or unsubstituted.

When used herein the term `aryl` includes phenyl and naphthyl optionallysubstituted with up to five, preferably up to three, groups selectedfrom halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro,carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, oralkylcarbonyl groups.

When used herein the term `halogen` refers to fluorine, chlorine,bromine and iodine; preferably chlorine.

When used herein the terms `alkyl` and `alkoxy` relate groups havingstraight or branched carbon chains, containing up to 12 carbon atoms.

Suitable alkyl groups are C₁ -₁₂ alkyl groups, especially C₁ -₆ alkylgroups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl ortert-butyl groups.

Suitable substituents for any alkyl group include those indicated abovein relation to the term "aryl".

When used herein the term `acyl` refers to organic acyl groups such asalkylcarbonyloxy groups for example C₁ -₆ alkylcarbonyloxy groups.

Suitable pharmaceutically acceptable salts include salts of theoxazolidinedione moiety, and, where appropriate, salts of carboxygroups.

Suitable pharmaceutically acceptable salts of the oxazolidinedionemoiety include metal salts especially alkali metal salts such as thelithium, sodium and potassium salts.

Suitable pharmaceutically acceptable salts of carboxy groups includemetal salts, such as for example aluminium, alkali metal salts such assodium or potassium, alkaline earth metal salts such as calcium ormagnesium and ammonium or substituted ammonium salts, for example thosewith lower alkylamines such as triethylamine, hydroxy alkylamines suchas 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine ortri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine,or with procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine,dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine,N-methylglucamine or bases of the pyridine type such as pyridine,collidine or quinoline.

Suitable pharmaceutically acceptable solvates include hydrates.

In a further aspect the present invention also provides a process forthe preparation of a compound of formula (I), or a tautomeric formthereof, and/or a pharmaceutically acceptable salt thereof, and/orapharmaceutically acceptable hydrate thereof, which process comprisesreacting a compound of formula (III): ##STR7## wherein A² is as definedin relation to formula (I), L¹ is a hydrogen atom or a protecting group,and R^(a) is a moiety convertible to a moiety of formula (f): ##STR8##wherein R¹, A¹ and n are as defined in relation to formula (I) with anappropriate reagent capable of converting R^(a) to the said moiety (f)and thereafter, if required, carrying out one or more of the followingoptional steps:

(i) converting a compound of formula ( I ) to a further compound offormula (I);

(ii) preparing a pharmaceutically acceptable salt of the compound offormula (I) and/or a pharmaceutically acceptable solvate thereof.

Suitably, R^(a) represents R¹ HN--(CH₂)_(n) --O--wherein R¹ and n are asdefined in relation no formula (I) or R^(a) represents a hydroxyl group.

When R^(a) is R¹ HN--(CH₂)_(n) --O--, an appropriate reagent capable ofconverting R^(a) to a moiety (f) is a compound of formula (IV):

    A.sup.1 --R.sup.x                                          (IV)

wherein A¹ is as defined in relation to formula (I) and R^(x) representsa leaving group.

A suitable leaving group R^(x) includes a halogen atom, preferably achlorine or bromine atom, or a thioalkyl group for example a thiomethylgroup.

Preferably, L¹ represents a protecting group, suitably a benzyl group.

The reaction between the compound of formula (III) and the appropriatereagent may be carried out under conditions suitable to the particularcompound of formula (III) and the reagent chosen. Thus for example theabovementioned reaction between a compound of formula (III) whereinR^(a) represents R¹ HN--(CH₂)_(n) --O-- and the compound of formula(IV), may be carried out in any suitable solvent, for exampletetrahydrofuran, at a temperature in the range of between 0° and 60° C.

Conversions of R^(a) to the moiety of formula (f) may be effected viasingle step or multiple step conversions, using appropriate conventionalchemistry.

Examples of multiple step conversions include the conversion of R^(a)when representing a hydroxyl group into a moiety R¹ HN--(CH₂)_(n) --O--and thereafter conversion to the moiety (f).

Thus, when R^(a) represents OH the conversion of R^(a) into R¹HN(CH₂)_(n) --O-- may conveniently be carried out by coupling a compoundof the abovedefined formula (III)with a compound of formula (V):

    R.sup.1 NR.sup.y (CH.sub.2).sub.n --OH                     (V)

wherein R¹ and n are as defined in relation to formula (I) and R^(y) ishydrogen or a nitrogen protecting group, in the presence of a suitablecoupling agent; and thereafter, if required, removing any nitrogenprotecting group.

A suitable coupling agent for the coupling reaction between the compoundof formula (III) and (V) is provided by diethylazodicarboxylate andtriphenylphosphine. The coupling reaction may be carried out in anysuitable solvent at a low to medium temperature, for example intetrahydrofuran at a temperature in the range of between 0° and 60° C.

Conversion of R¹ HN--(CH₂)_(n) --O-- into a moiety of formula (f) may beeffected as described above.

Alternatively, when R^(a) is hydroxyl, conversion into a moiety offormula (f) is suitably effected by treating the compound of theabovedefined formula (III) with a compound of formula (VI): ##STR9##wherein A¹, R¹ and n are as defined in relation to formula (I) and R^(z)represents hydrogen or a tosylate or mesylate group.

The reaction between the compound of formula (III) wherein R^(a) is ahydroxyl group and the reagent of the abovedefined formula (VI), whenR^(z) is hydrogen, may suitably be carried out in an aprotic solvent,such as tetrahydrofuran, at low to medium temperature, for example atambient temperature, and preferably in the presence of a coupling agentsuch as that provided by triphenylphosphine and diethylazodicarboxylate.

The reaction between the compound of formula (III), wherein R^(a) is ahydroxyl group, and the reagent of the abovedefined formula (VI) whenR^(z) is tosylate or mesylate may be carried out in an aprotic solvent,such as dimethylformamide, at a low to elevated temperature, for examplein the range of from 50° C. to 120° C. and preferably in the presence ofa base, such as sodium hydride.

The compound of formula (VI) when R^(z) is tosylate or mesylate may beprepared from the corresponding compound of formula (VI) when R^(z) ishydrogen by reaction with either a tosyl halide or a mesyl halide in asolvent such as pyridine.

The reagent of formula (VI) may be prepared by reacting a compound ofthe hereinabove defined formula (IV), with a compound of thehereinbefore defined formula (V) and thereafter if required removing anynitrogen protecting group using the appropriate conventional conditions.

The reaction between the compounds of formula (IV) and (V) may becarried out under any suitable conditions, such as in solvent, forexample in an aprotic solvent such as tetrahydrofuran, at a low tomedium temperature, for example a temperature in the range of from 0° to60° C.

Favourably when R¹ represents hydrogen the reaction is carried out usingthe compound of formula (V) as a solvent at a low to elevatedtemperature, suitably an elevated temperature such as in the range ofbetween 100° and 170° C.

A compound of formula (III) wherein R^(a) is OH may be prepared byreacting a compound of formula (VII): ##STR10## wherein A₂ is as definedin relation to formula (I), R¹⁰ represents a hydroxyl group or aprotected hydroxyl group and R¹¹ represents a group or moietyconvertible into an oxazolidinedione group, with a reagent capable ofconverting a moiety R¹¹ into an oxazolidinedione group; and thereafterif required removing any protecting group.

Suitably, R¹⁰ represents a protected hydroxy group, for example abenzyloxy group.

Suitably R¹¹ represents a moiety of formula (g): ##STR11## wherein R¹²represents a C₁ -₆ alkyl group, suitably a methyl group.

When R¹¹ represents a moiety of formula (g), a suitable reagent is urea.

Reaction conditions for the reaction between the compound of formula(VII) and the reagent will of course depend upon the particular natureof R¹¹ and the reagent, for example when R¹¹ is a moiety of formula (g)and the reagent is urea, the reaction may be carried out in an alkanoicsolvent, such as ethanol, at any temperature providing an acceptablerate of formation of the required product, for example an elevatedtemperature, preferably the reflux temperature of the solvent;preferably the reaction is effected in the presence of a base, such as aalkali metal alkoxide, for example sodium methoxide, followed bytreatment with a dilute mineral acid, for example dilute hydrochloricacid.

The compounds of formula (VII) are known compounds or they may beprepared according to methods used to prepare known compounds, forexample the compounds of formula (VII) wherein R¹¹ is a moiety (g) maybe prepared according to methods disclosed in Chem. Pharm. Bull. 30.(1982), 3563.

The abovementioned conversion of a compound of formula (I) into afurther compound of formula (I) includes the conversion of one group R¹into another group R¹.

The conversion of a compound of formula (I) to a further compound offormula (I) may be carried out by using any appropriate conventionalprocedure.

Suitable conversions of one group R¹ into another group R¹ includesconverting hydrogen into an acyl group.

The conversion of a compound of formula (I) wherein R¹ representshydrogen into a compound of formula (I) wherein R¹ represents acyl maybe carried out using any appropriate conventional acylation procedure,such as by treating an appropriately protected compound of formula (I)with an acylating agent. For example acetic anhydride may be used toprepare the compound of formula (I) wherein R¹ is acetyl.

The compounds of formula (IV) and (V) are known commercially availablecompounds or are prepared using methods analogous to those used toprepare known compounds.

Suitable protecting groups in any of the abovementioned reactions arethose used conventionally in the art. Thus, for example, a suitablenitrogen protecting group is a benzyl group or a benzyloxycarbonyl groupand a suitable hydroxyl protecting group is a benzyl group.

The methods of formation and removal of such protecting groups are thoseconventional methods appropriate to the molecule being protected. Thusfor example a benzyloxy group may be prepared by treatment of theappropriate compound having a hydroxyl group with a benzyl halide, suchas benzyl bromide, and thereafter when required the benzyl group may beconveniently removed using a mild ether cleavage reagent such astrimethylsilyliodide.

Where appropriate the isomeric forms of the compounds of formula (I) andthe pharmaceutically acceptable salts thereof may be prepared asindividual isomers using conventional chemical procedures.

As mentioned above the compounds of the invention are indicated ashaving useful therapeutic properties:

The present invention accordingly provides a compound of formula (I), ora tautomeric form thereof and/or a pharmaceutically acceptable saltthereof and/or a pharmaceutically acceptable solvate thereof, for use asan active therapeutic substance.

Thus the present invention provides a compound of formula (I), or atautomeric form thereof and/or a pharmaceutically acceptable saltthereof and/or a pharmaceutically acceptable solvate thereof, for use inthe treatment of and/or prophylaxis of hyperglycaemia.

In a further aspect the present invention also provides a compound offormula (I), or a tautomeric form thereof and/or a pharmaceuticallyacceptable salt thereof and/or a pharmaceutically acceptable solvatethereof, for use in the treatment and/or prophylaxis of hyperlipidaemia.

As indicated hereinbefore the present invention also provides a compoundof formula (I) or a tautomeric form thereof and/or a pharmaceuticallyacceptable salt thereof and/or a pharmaceutically acceptable solvatethereof for use in the treatment of hypertension, cardiovascular diseaseand certain eating disorders.

A compound of formula (I), or a tautomeric form thereof and/or apharmaceutically acceptable salt thereof and/or a pharmaceuticallyacceptable solvate thereof, may be administered per se or, preferably,as a pharmaceutical composition also comprising a pharmaceuticallyacceptable carrier.

Accordingly, the present invention also provides a pharmaceuticalcomposition comprising a compound of the general formula (I), or atautomeric form thereof, or a pharmaceutically acceptable salt thereof,or a pharmaceutically acceptable solvate thereof, and a pharmaceuticallyacceptable carrier therefor.

As used herein the term `pharmaceutically acceptable` embracescompounds, compositions and ingredients for both human and veterinaryuse: for example the term `pharmaceutically acceptable salt` embraces aveterinarily acceptable salt.

The composition may, if desired, be in the form of a pack accompanied bywritten or printed instructions for use.

Usually the pharmaceutical compositions of the present invention will beadapted for oral administration, although compositions foradministration by other routes, such as by injection and percutaneousabsorption are also envisaged.

Particularly suitable compositions for oral administration are unitdosage forms such as tablets and capsules. Other fixed unit dosageforms, such as powders presented in sachets, may also be used.

In accordance with conventional pharmaceutical practice the carrier maycomprise a diluent, filler, disintegrant, wetting agent, lubricant,colourant, flavourant or other conventional adjuvant.

Typical carriers include, for example, microcrystalline cellulose,starch, sodium starch glycollate, polyvinylpyrrolidone,polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulphate orsucrose.

Most suitably the composition will be formulated in unit dose form. Suchunit dose will normally contain an amount of the active ingredient inthe range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and moreespecially 0.1 to 250 mg.

The present invention further provides a method for the treatment and/orprophylaxis of hyperglycaemia in a human or non-human mammal whichcomprises administering an effective, non-toxic, amount of a compound ofthe general formula (I), or a tautomeric form thereof and/or apharmaceutically acceptable salt thereof and/or a pharmaceuticallyacceptable solvate thereof to a hyperglycaemic human or non-human mammalin need thereof.

The present invention further provides a method for the treatment ofhyperlipidaemia in a human or non-human mammal, which comprisesadministering an effective, non-toxic, amount of a compound of formula(I), or a tautomeric form thereof and/or a pharmaceutically acceptablesalt thereof and/or a pharmaceutically acceptable solvate thereof, to ahyperlipidaemic human or non-human mammal in need thereof.

Conveniently, the active ingredient may be administered as apharmaceutical composition hereinbefore defined, and this forms aparticular aspect of the present invention.

In the treatment and/or prophylaxis of hyperglycaemic humans, and/or thetreatment and/or prophylaxis of hyperlipidaemic human, the compound ofthe general formula (I), or a tautomeric form thereof and/or apharmaceutically acceptable salt thereof and/or a pharmaceuticallyacceptable solvate thereof, may be taken in doses, such as thosedescribed above, one to six times a day in a manner such that the totaldaily dose for a 70 kg adult will generally be in the range of from 0.1to 6000 mg, and more usually about 1 to 1500 mg.

In the treatment and/or prophylaxis of hyperglycaemic non-human mammals,especially dogs, the active ingredient may be adminstered by mouth,usually once or twice a day and in an amount in the range of from about0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg. Similardosage regimens are suitable for the treatment and/or prophylaxis ofhyperlipidaemia in non-human mammals.

The dosages regimens for the treatment of hypertension, cardiovasculardisease and eating disorders will generally be those mentioned above inrelation to hyperglycaemia.

In a further aspect the present invention provides the use of a compoundof formula (I), or a tautomeric form thereof and/or a pharmaceuticallyacceptable salt thereof and/or a pharmaceutically acceptable solvatethereof, for the manufacture of a medicament for the treatment and/orprophylaxis of hyperglycaemia.

The present invention also provides the use of a compound of formula(I), or a tautomeric form thereof and/or a pharmaceutically acceptablesalt thereof, and/or a pharmaceutically acceptable solvate thereof, forthe manufacture of a medicament for the treatment and/or prophylaxis ofhyperlipidaemia, hypertension, cardiovascular disease or certain eatingdisorders.

The following Procedures and Examples illustrate the invention but donot limit it in any way.

EXAMPLE 15-(4-[2-((N-methyl-N-(2-benzoxazolyl)amino)ethoxy]-benzyl)-2,4-oxazolidinedione##STR12## Sodium hydride (0.85 g; 60% dispersion in oil) was addedportionwise to a stirred solution of5-[(4-hydroxy)benzyl]oxazolidine-2,4-dione (2 g) in dry DMF (65 ml)under an atmosphere of nitrogen. After effervescence had ceased,2-(N-(2-benzoxazolyl)-N-methylamino)ethanol methanesulphonyl ester (2.73g) was added and the solution heated to 80° C. overnight. After coolingthe mixture was added to water (400 ml), neutralised (2M HCl) andextracted with ethyl acetate (3×200 ml). The combined organic extractswere washed with water (100 ml), brine (2×100 ml), dried (MgSO₄) andevaporated to dryness. Chromatography of the residue on silica gel in 1%methanol in dichloromethane afforded the title compound (m.p. 173°-4°C.; MeOH).

¹ H NMR δ (DMSO-d₆) 2.9-3.15 (2H, complex); 3.2 (3H, s); 3.85 (2H, t);4.25 (2H, t); 5.2 (1H, complex); 6.8-7.4 (8H, complex); 11.7 (1H, broads, exchanges with D₂ O).

PREPARATION 1 Methyl 2-chloro-3-(4-benzyloxy)phenylpropionate ##STR13##To a cooled (below 5° C.) and stirred suspension of (4-benzyloxy)aniline hydrochloride (12 g) in acetone (120 ml), 1,4-dioxan (20 ml) andconcentrated hydrochloric acid (11 ml) was added dropwise a solution ofsodium nitrite (4 g) in water (10 ml) over a period of 10 minutes. Thesuspension was stirred below 5° C. for a further 30 minutes, then methylacrylate (28 ml) was added dropwise over 2 minutes, and the suspensionallowed to warm to 30° C. Copper (I) iodide (0.3 g) was now addedportionwise to the mixture, which was left to stir for a further hour.Excess solvent was evaporated off, the residue partitioned between water(500 ml and ethyl acetate, the organic extracts (3×200 ml) combined andwashed with dilute ammonia solution (2×200 ml), water (200 ml) , brine(200 ml), dried (MgSO₄), filtered and evaporated to dryness. The titlecompound was obtained as an oil.

¹ H NMR δ (CDCl₃) 3.0-3.45 (2H, complex); 3.8 (3H, s); 4.45 (1H, t); 5.1(2H, s); 6.95 (2H, d); 7.25 (2H, d); 7.5 (5H, complex).

PREPARATION 2 2-Hydroxy-3-(4-benzyloxy)phenylpropionic acid ##STR14##Methyl-2-chloro-3-(4-benzyloxy)phenylpropionate (9g),sodium hydroxide(1.27 g) and calcium carbonate (2.95 g) were refluxed in a mixture of1,4-dioxan (50 ml) and water (80 ml) for 16 hours. After cooling themixture was acidified (2M HCl; 200 ml) and extracted with ethyl acetate(2×200 ml). The combined organic extracts were washed with brine (2×100ml) , dried (MgSO₄) , filtered and evaporated. The title compound (mp145°-5° C.) was obtained following recrystallization of the organicresidues from ethyl acetate/hexane.

¹ H NMR δ (CDCl₃ +DMSO-d₆) 2.6-3.1 (2H, complex); 4.2 (1H, complex); 5.0(2H, s); 6.8-6.9 (2H, d); 7.1-7.5 (7H, complex); 6.7-8.0 (2H, v broad s;exchanges with D₂ O).

PREPARATION 3 Ethyl 2-hydroxy-3-(4-benzyloxy)phenylpropionate ##STR15##2-hydroxy-3-(4-benzyloxy)phenylpropionic acid (4 g) and concentratedhydrochloric acid (0.1 ml) were refluxed in ethanol (70 ml) for 16hours. The solution was cooled, added to water (400 ml) and extractedwith ethyl acetate (2×200 ml). The combined organic extracts were washedwith brine (2×100 ml), dried (MgSO₄), filtered and evaporated to drynessto afford the title compound, which was used in the next stage withoutfurther purification.

¹ H NMR δ (CDCl₃) 1.3 (3H, t), 2.8 (1H, broad s, exchanges with D₂ O),2.8-3.2 (2H, complex); 4.2 (2H, q); 4.35 (1H, multipier); 5.1 (2H, s);6.9 (2H, d); 7.2 (2H, d); 7.45 (5H, s).

PREPARATION 4 5-[(4-Benzyloxy)benzyl]oxazolidine-2,4-dione. ##STR16## Asolution of ethyl 2-hydroxy-3-(4-benzyloxy)phenylpropionate (4.5 g),urea (1.62 g) and sodium methoxide (1.13 g) in a mixture of methanol (4ml) and ethanol (40 ml) was stirred for 2 hours at room temperature,then refluxed for 3 hours. After cooling, the mixture was added tohydrochloric acid (2M; 260 ml) and extracted with ethyl acetate (2×250ml). The combined organic extracts were washed with water (200 ml),brine (200 ml), dried (MgSO₄), filtered and evaporated to dryness. Theresidue was chromatographed on silica gel in 5% methanol indichloromethane to afford the title compound (m.p.140° C.).

¹ H NMR δ (CDCl₃ +DMSO-d₆) 2.9-3.3 (2H, complex); 5.0 (1H, t); 5.05 (2H,s); 6.85-7.0 (2H, d); 7.1-7.25 (2H, d); 7.45 (5H, s) 7.2-7.7 (1H, broads, exchanges with D₂ O).

PREPARATION 5 5-[(4-Hydroxy)benzyl]oxazolidine-2,4-dione. ##STR17## Asolution of 5-[4-benzyloxy)benzyl]-oxazolidine-2,4-dione (4.7 g) in dry1,4-dioxan (70 ml) in the presence of 10% palladium on charcoal (0.25 g)was stirred under an atmosphere of hydrogen at ambient temperature untilhydrogen uptake ceased. The solution was filtered through diatomaceousearth, the filter pad was washed exhaustively with dioxan, and thecombined filtrates evaporated to dryness under vacuum. The residue waschromatographed on silica-gel in 10% methanol in dichloromethane toafford the title compound (m.p. 205° C.).

NMR δ (DMSO-d₆) 2.8-3.2 (2H, complex); 5.2 (1H, t); 6.65-6.75 (2H, d);7.0-7.1 (2H, d); 9.5 (2H, broad s, exchanges with D₂ O).

DEMONSTRATION OF EFFICACY OF COMPOUNDS Obese Mice, Oral GlucoseTolerance Test.

C57 bl/6 obese (ob/ob) mice were fed on powdered oxoid diet. After atleast one week, the mice continued on a powdered oxoid diet or were fedpowdered oxoid diet containing the test compound. After 8 days on thesupplemented diet all of the mice were fasted for 5 hours prior toreceiving an oral load of glucose (3 g/kg). Blood samples for glucoseanalysis were taken 0, 45, 90 and 135 minutes after glucoseadministration and the results appear below as the percentage reductionin area under the blood glucose curve where test compound treated groupsare compared with the control groups. 7 mice were used for eachtreatment.

    ______________________________________                                                 LEVEL IN DIET  % REDUCTION IN                                        EXAMPLE  (μmol kg.sup.-1 of                                                                        AREA UNDER BLOOD                                      NO:      DIET)          GLUCOSE CURVE                                         ______________________________________                                        1        300            41                                                    ______________________________________                                    

Toxicology

No toxicological effects were indicated for any of the compounds of theinvention in any of the abovementioned tests.

I claim:
 1. A compound of formula (I): ##STR18## or a tautomeric formthereof and/or a pharmaceutically acceptable salt thereof, and/or apharmaceutically acceptable solvate thereof, wherein:A¹ represents asubstituted or unsubstituted oxazole substituted by up to 4 substituentsselected from the group consisting of C₁₋₆ -alkyl, C₁₋₆ -alkoxy, phenyland halogen or any two substituents on adjacent carbon atoms, togetherwith the carbon atoms to which they are attached, form a benzene ring,and wherein the carbon atoms of the benzene ring represented by the saidtwo substituents are unsubstituted or substituted with up to threegroups selected from halogen, C₁₋₆ -alkyl, phenyl, C₁₋₆ -alkoxy,halo-C₁₋₆ -alkyl, hydroxy, amino, nitro, carboxy, C₁₋₆ -alkoxycarbonyl,C₁₋₆ -alkoxycarbonyl-C₁₋₆ -alkyl, C₁₋₆ -alkylcarbonyloxy and C₁₋₆-alkylcarbonyl; R¹ represents a hydrogen atom, a C₁₋₆ -alkyl group, aC₁₋₆ -alkylcarbonyloxy group, a phenyl-C₁₋₆ -alkyl group, wherein thephenyl moiety may be substituted or unsubstituted, or a substituted orunsubstituted phenyl group, wherein the said phenyl groups may besubstituted with up to three groups selected from halogen, C₁₋₆ -alkyl,phenyl, C₁₋₆ -alkoxy, halo-C₁₋₆ -alkyl, hydroxy, amino, nitro, carboxy,C₁₋₆ -alkoxycarbonyl, C₁₋₆ -alkoxycarbonyl-C₁₋₆ -alkyl, C₁₋₆-alkylcarbonyloxy and C₁₋₆ -alkylcarbonyl; A² represents a benzene ringhaving in total up to five substituents wherein three optionalsubstitutents are selected from halogen, C₁₋₆ -alkyl, phenyl, C₁₋₆-alkoxy, halo-C₁₋₆ -alkyl, hydroxy, amino, nitro, carboxy, C₁₋₆-alkoxycarbonyl, C₁₋₆ -alkoxycarbonyl-C₁₋₆ -alkyl, C₁₋₆-alkylcarbonyloxy and C₁₋₆ -alkylcarbonyl; and n represents an integerfrom 2 to
 6. 2. A compound according to claim 1, wherein A¹ represents amoiety of formula (a): ##STR19## wherein X represents oxygen; R⁴ and R⁵each independently represents a hydrogen atom, a C₁₋₆ -alkyl group, aphenyl group or a phenyl group substituted with up to three groupsselected from halogen, C₁₋₆ -alkyl, phenyl, C₁₋₆ -alkoxy, halo-C₁₋₆-alkyl, hydroxy, amino, nitro, carboxy, C₁₋₆ -alkoxycarbonyl, C₁₋₆-alkoxycarbonyl-C₁₋₆ -alkyl, C₁₋₆ -alkylcarbonyloxy and C₁₋₆-alkylcarbonyl; or when R⁴ and R⁵ are each attached to adjacent carbonatoms, then R⁴ and R⁵ together with the carbon atoms to which they areattached form a benzene ring wherein each carbon atom represented by R⁴and R⁵ together may be unsubstituted or unsubstituted with up to threegroups selected from halogen, C₁₋₆ -alkyl, phenyl, C₁₋₆ -alkoxy,halo-C₁₋₆ -alkyl, hydroxy, amino, nitro, carboxy, C₁₋₆ -alkoxycarbonyl,C₁₋₆ -alkoxycarbonyl-C₁₋₆ -alkyl, C₁₋₆ -alkylcarbonyloxy and C₁₋₆-alkylcarbonyl.
 3. A compound according to claim 1, wherein R⁴ and R⁵together represent a moiety of formula (d): ##STR20## wherein R⁶ and R⁷each independently represent hydrogen, halogen, C₁₋₆ -alkyl, C₁₋₆-alkoxy, or C₁₋₆ -alkyl or C₁₋₆ -alkoxy substituted with up to three,groups selected from halogen, C₁₋₆ -alkyl, phenyl, C₁₋₆ -alkoxy,halo-C₁₋₆ -alkyl, hydroxy, amino, nitro, carboxy, C₁₋₆ -alkoxycarbonyl,C₁₋₆ -alkoxycarbonyl-C₁₋₅ -alkyl, C₁₋₆ -alkylcarbonyloxy and C₁₋₆-alkylcarbonyl.
 4. A compound according to claim 1, wherein A²represents a moiety of formula (e): ##STR21## wherein R⁸ and R⁹ eachindependently represent hydrogen, halogen, C₁₋₆ -alkyl, C₁₋₆ -alkoxy, orC₁₋₆ -alkyl or C₁₋₆ alkoxy substitutedwith up to three, groups selectedfrom halogen, C₁₋₆ -alkyl, phenyl, C₁₋₆ -alkoxy, halo-C₁₋₆ -alkyl,hydroxy, amino, nitro, carboxy, C₁₋₆ -alkoxycarbonyl, C₁₋₆-alkoxycarbonyl-C₁₋₆ C₁₋₆ -alkylcarbonyloxy, and C₁₋₆ -alkylcarbonyl. 5.A compound according to claim 1, of formula (II): ##STR22## or atautomeric form thereof, and/or a pharmaceutically acceptable saltthereof and/or a phamaceutically acceptable solvate thereof, wherein A¹,R¹ and n are as defined in relation to formula (I) and R⁸ and R⁹ eachindependently represent hydrogen, halogen, C₁₋₆ -alkoxy, C₁₋₆ -alkyl orC₁₋₆ -alkyl substituted with up to three groups selected from halogen,C₁₋₆ -alkyl, phenyl, C₁₋₆ -alkoxy, halo-C₁₋₆ -alkyl, hydroxy, amino,nitro, carboxy, C₁₋₆ -alkoxycarbonyl, C₁₋₆ -alkoxycarbonyl-C₁₋₆ -alkyl,C₁₋₆ -alkylcarbonyloxy, and C₁₋₆ -alkylcarbonyl.
 6. A compound accordingto claim 1, wherein n represents an integer 2, 3 or
 4. 7. A compoundaccording to claim 1, being5-(4-[2-((N-methyl-N-(2-benzoxazolyl)amino)ethoxy]benzyl)-2,4-oxazolidinedione;or a tautomeric form thereof or a pharmaceutically acceptable saltthereof, or a pharmaceutically acceptable solvate thereof.
 8. Apharmaceutical composition comprising a compound according to claim 1,or a tautomeric form thereof, or a pharmaceutically acceptable saltthereof, or a pharmaceutically acceptable solvate thereof, and apharmaceutically acceptable carrier therefor.
 9. A method for thetreatment and/or prophylaxis of hyperglycaemia or hyperlipidaemia in ahuman or non-human mammal which comprises administering an effective,non-toxic amount of a compound of formula (I), or a tautomeric formthereof and/or a pharmaceutically acceptable salt thereof and/or apharmaceutically acceptable solvate thereof to a hyperglycaemic human ornon-human mammal in need thereof.